An evolutionarily conserved intronic region controls the spatiotemporal expression of the transcription factor Sox10.
BACKGROUND
A major challenge lies in understanding the complexities of gene regulation. Mutation of the transcription factor SOX10 is associated with several human diseases. The disease phenotypes reflect the function of SOX10 in diverse tissues including the neural crest, central nervous system and otic vesicle. As expected, the SOX10 expression pattern is complex and highly dynamic, but little is known of the underlying mechanisms regulating its spatiotemporal pattern. SOX10 expression is highly conserved between all vertebrates characterised.


RESULTS
We have combined in vivo testing of DNA fragments in zebrafish and computational comparative genomics to identify the first regulatory regions of the zebrafish sox10 gene. Both approaches converged on the 3' end of the conserved 1st intron as being critical for spatial patterning of sox10 in the embryo. Importantly, we have defined a minimal region crucial for this function. We show that this region contains numerous binding sites for transcription factors known to be essential in early neural crest induction, including Tcf/Lef, Sox and FoxD3. We show that the identity and relative position of these binding sites are conserved between zebrafish and mammals. A further region, partially required for oligodendrocyte expression, lies in the 5' region of the same intron and contains a putative CSL binding site, consistent with a role for Notch signalling in sox10 regulation. Furthermore, we show that beta-catenin, Notch signalling and Sox9 can induce ectopic sox10 expression in early embryos, consistent with regulatory roles predicted from our transgenic and computational results.


CONCLUSIONS
We have thus identified two major sites of sox10 regulation in vertebrates and provided evidence supporting a role for at least three factors in driving sox10 expression in neural crest, otic epithelium and oligodendrocyte domains.
Dutton
James R
JR
Centre for Regenerative Medicine, Department of Biology and Biochemistry, University of Bath, Bath, BA2 7AY, UK. dutto015@umn.edu
Antonellis
Anthony
A
Carney
Thomas J
TJ
Rodrigues
Frederico S L M
FS
Pavan
William J
WJ
Ward
Andrew
A
Kelsh
Robert N
RN
D000818:Animals; D030801:Animals, Genetically Modified; D001665:Binding Sites; D005075:Biological Evolution; D017124:Conserved Sequence; D005854:Germ Cells; D049452:Green Fluorescent Proteins / Q000235:genetics; D007438:Introns; D011401:Promoter Regions, Genetic; D012045:Regulatory Sequences, Nucleic Acid; D055757:SOXE Transcription Factors / Q000235:genetics* / Q000378:metabolism; D015027:Zebrafish / Q000196:embryology / Q000235:genetics*; D029961:Zebrafish Proteins / Q000235:genetics* / Q000378:metabolism
D055757:SOXE Transcription Factors; D029961:Zebrafish Proteins; C442229:sox10 protein, zebrafish; D049452:Green Fluorescent Proteins